Candidate: Shridar Ganesan's career goal is to become an independent cancer researcher focused on the biology of breast cancer with a specific interest in the BRCA1 tumor suppressor gene and its involvement in the regulation of chromatin structure. This basic research in the mechanism of breast cancer development will be complemented by his clinical involvement in the care of breast cancer patients. The Howard Temin Award will assist his transition to a fully independent position as scientific investigator and faculty member. His mentorship by Dr. David Livinston over the next several years will be critical for refining his research skills and establishing a presence in the field of BRCA1 biology, and thus, allow a smooth transition to an independent research position. Environment: The Dana-Farber Cancer Institute and Harvard Medical School provide an excellent environment with the resources and collaborative opportunities required for the completion of the research goals outline in this proposal. His mentor Dr. Livingston has an outstanding record as an excellent mentor and his laboratory provides a stimulating, supportive, and productive intellectual and scientific environment. Research: The hypothesis and specific aims are: Hypothesis: BRCA1 interacts with XlST RNA and is required for proper maintenance of chromatin structure necessary for silencing of the inactive X chromosome. BRCA1 may interact similarly with other RNA species to participate in regulation of chromatin structure elsewhere in the genome. Specific Aims: 1. Identify and characterize the regions of interaction between BRCA1 and XIST RNA. 2. Determine the effects of BRCA1 loss on the state of histone methylation of the inactive X chromosome. 3. Determine if BRCA1 interacts with other RNA species besides XIST RNA.